1. Field of the Invention
The present invention relates to sustained release compositions containing and releasing pyriproxifen, 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine, and the use of such compositions for control of ectoparasitic insects on homoiothermic or warm-blooded animals and in another embodiment, the use of combinations of pyriproxifen with insecticidal and acaricidal toxicant active ingredients in sustained release compositions to control both ectoparasitic insects and ectoparasitic acarines.
2. Background
Blood sucking ectoparasites of the class Insecta include fleas, such as Ctenocephalides felis and Ctenocephalides canis (cat and dog fleas), as well as lice, mosquitos, tabanids, tsetse and other biting flies and those of the class Aricana include ticks such as Boophilus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, lxodes, Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and mites. These ectoparasites infest or attack many useful homoiothermic animals, including farm animals such as cattle, swine, sheep, goats, poultry such as chickens, turkeys and geese, fur bearing animals such as mink, foxes, chinchilla, rabbits, and pet animals such as dogs and cats.
Ticks are described as hard ticks or soft ticks and are characterized as one host, two host, or three host ticks. They attach to a suitable host animal and feed on blood and body fluids. Engorged females detach and drop from the host and lay large numbers of eggs (2,000 to 20,000) in a suitable niche in the ground or in some other sheltered location in which hatching occurs. The larvae then seek hosts from which to obtain blood meals. Larvae of one host ticks molt on the host twice to become nymphs and adults without leaving the host. Larvae of two and three host ticks drop off the host, molt in the environment and find a second or third host (as nymph or adult) on which to feed.
Ticks are responsible for the transmission and propagation of many human and animal diseases throughout the world. Ticks of major economic importance include Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma, and Dermacentor. They are vectors of bacterial, viral, rickettsial and protozoal diseases, and cause tick paralysis and tick toxicosis. Even a single Ixodes holocyclus tick can cause paralysis consequent to injecting its saliva into its host in the feeding process. Tick-borne diseases are usually transmitted by multiple-host ticks. Such diseases, including Babesiosis, Anaplasmosis, Theileriosis and Heart Water are responsible for the death and/or debilitation of vast numbers of pet and food animals throughout the world. In many temperate countries, Ixodid ticks transmit the agent of a chronic, debilitating disease, Lyme disease, from wildlife to man and to his pets. In addition to disease transmission, ticks are responsible for great economic losses in livestock production. Losses are attributable not only to death, but also to damage of hides, loss of growth, reduction in milk production, and reduced grade of meat. Although the debilitating effects of tick infestations on animals have been recognized for years and tremendous advances have been made in tick control programs, no entirely satisfactory methods for controlling or eradicating these parasites have been forthcoming, and ticks have often developed resistance to chemical toxicants.
Infestation of pets by fleas has long been a nuisance to pet owners. Because fleas are able to survive and multiply under a wide range of environmental conditions, controlling flea infestation requires a multi-faceted program that must be vigorously applied to achieve any measure of success.
Adult fleas live in the coat of the cat or dog and feed on blood. Male and female fleas mate while still in the animal's coat. When the female flea lays her eggs, the eggs do not adhere to the fur, but fall off and are distributed to the animal's environment. By this mechanism, while the total environment of the pet animal is infested with flea eggs, infestation is greatest in locations where the pet spends most of its time. Eggs hatch to larvae in about two days. There are three larval stages, each lasting about three days. In the last stage, the larva spins a cocoon and transforms into a pupa. Under optimum conditions (i.e., 33.degree. C. and 65% relative humidity), eggs develop through larvae to pupae in about 8-10 days. After a further period of approximately 8 days, the pupae develop into young adult fleas in the cocoon, still dispersed in the pet's environment. These pre-emerged adult fleas wait in their pupae until they sense, by carbon dioxide tension and/or vibrations, the presence of an animal host, and then emerge explosively and jump into the air and onto the passing host.
Under suitable environmental conditions of temperature and humidity, unfed emerged fleas that fail to find a host can survive for some time in the environment, waiting for a suitable host. It thus takes at least three weeks for eggs to develop to pre-emerged adults, able to reinfest a host animal. However, the pre-emerged adults can remain viable in the cocoon for months, as long as one year. In addition, under sub-optimal temperature conditions, it can take 4-5 months for eggs to develop into pupae containing pre-emerged adults.
Fleas require a blood meal in order to become sexually mature and able to reproduce. After their first blood meal, they undergo a shift in metabolism such that they cannot survive for any time off the host. The blood must come from the correct animal and the female flea's appetite requires that she consumes as much as 5 times her body weight of blood each day. The long life cycle, and especially the extended period of pre-emergence dormancy, has made flea control with compounds applied topically to pet animals difficult and not entirely satisfactory. Most topically applied active ingredients have limited residual effect, thus reinfestation by newly-emerged adult fleas from the pet's environment is a constant problem.
Infestation of dogs and cats with fleas has several undesirable effects for the animals and for their owners. Such undesirable effects include local irritation and annoying itching, leading to scratching. A high proportion of pet animals, particularly dogs, become allergic to flea saliva, resulting in the chronic condition known as flea bite allergy (or flea allergy). This condition causes the animal to bite and scratch, leading to excoriation of the skin, secondary pyrogenic infection, hair loss, and chronic severe inflammatory skin changes. Allergic pets may suffer severe skin reactions to the bite of even a few fleas. Furthermore, most dogs and cats that are infested with fleas also become infected with Dipylidium caninum, the tapeworm transmitted by fleas.
In prolonged absence of suitable animals, newly emerged fleas attack any mammal, including humans, although they are not capable of full reproductive potential if human blood is their sole source of nutrition. Even in the presence of the pet animal, the owner may be bitten by fleas. Some humans may suffer allergic skin disease as a result of being bitten by dog and cat fleas.
Since, like most insects, fleas can adapt to survive exposure to normal toxic agents, and the tolerance of dogs and cats to chemical agents varies, it is desirable to have a multiplicity of agents and methods available for controlling fleas. Prior art methods have included numerous toxic agents such as organophosphates (e.g., chlorpyrifos), carbamates (e.g., carbaryl), pyrethroids (e.g., natural pyrethrins and synthetic pyrethroids like permethrin), and other topical insecticides formulated and designed to kill the adult flea after their application to the pet. Many of the effective residual action toxic agents against fleas, such as DDT, benzene hexachloride, and other chlorinated hydrocarbon insecticides, have been banned from most countries because of environmental persistence of residues and their effect on certain wildlife. Others have been banned because of long-term health risks, including risks of cancer to chronically exposed humans. In the United States, even currently approved and available toxic agents that are effective against fleas, some only briefly, are under scrutiny because of concerns for long-term health hazards to pets and to their owners. These considerations have limited utility of insecticidal and acaricidal toxic compounds for control of fleas and ticks on pet animals and in their environments, and of ectoparasites on animals in general.
Single topical application of such insecticidal and acaricidal compounds, usually with synergists and repellents, are effective, and to avoid the inconvenience of frequently repeated applications of sprays, dips, pour-ons, shampoos, dusts and other topical delivery formulations, both residual compounds and initial higher dosages of potentially toxic compounds have been employed in formulations to extend the period of activity of single applications, and hence to reduce the frequency of application. However, the most stable residual compounds, (i.e., both toxicants and synergists) and the higher dosages have resulted in widespread toxic reactions in pet animals, including deaths. Some animals, particularly cats through their self-grooming activities, are much more prone to adverse reactions and there are few residual formulations that can be applied safely to the cat. This results in repeated applications that most cats find objectionable and resist vigorously, resulting in poor treatment compliance.
Due to the inconvenience and consequent failure of compliance by pet owners with the repeat treatment protocols that are necessary to achieve successful control of ectoparasites through sprays, pour-ons, dips, shampoos, dusts or other topical applications of toxicants, synergists, repellents and insect growth regulators; and similarly the difficulty of repeated daily oral dosage of tablets or other dose forms containing systemically active compounds for the control of ectoparasites on pet animals, particularly on cats, it is desirable that alternative, more convenient control systems with assured higher treatment compliance be made available.
The difficulty of topical application control methods has led to the development of controlled release devices such as solid plastic collars and medallions and plastic reservoirs containing insecticidal and acaricidal toxicants, some with synergists, in which the active ingredients are either incorporated into the solid plastic matrix or are present as liquid in the reservoir. The toxicants are released from the solid matrixes by diffusion to the surface. Toxicants that are liquid at ambient temperature diffuse through a rate limiting semi-permeable membrane from the plastic reservoir. Toxicants that are solid (e.g., powder) at ambient temperatures dissolve in the plasticizer and in any other liquid lipophilic solvents in the matrix and are by diffusion carried to the surface to become available to spread over the coat of the animal. Liquid toxicants in controlled release reservoir devices diffuse out through semi-permeable membranes and hence become available for spread over the coat of the animal. Toxicants with high vapor pressure (e.g., some organophosphates), when they reach the surface of the controlled release device achieve their insecticidal and acaricidal activities partially by evaporation to spread over the animal surface (and its environment) and partially by solution in the natural oils in the haircoat to spread by diffusion of these oils. Compounds with low vapor pressure (e.g., amitraz and synthetic pyrethroids) are spread only by solution in the oil of the haircoat.
The technology of formulating and manufacturing controlled release devices, such as collars, medallions and reservoirs for delivery of insecticidal and acaricidal toxicant compounds, is well-known in the literature. Topical applications of insect growth regulators generally are found, for example, in U.S. Pat. No. 5,221,535 and references cited therein. However, the insect growth regulators are applied, for example, as sprays that have to be applied repeatedly at intervals of a few days to at most one month. There is no disclosure of using insect growth regulators in sustained release compositions. Thus, the prior art does not suggest the possibility of employing a sustained release device in the topical application of pyriproxifen or pyriproxifen-like compounds.
The technology of formulating and manufacturing controlled release devices such as collars, medallions and reservoirs for the delivery of insecticidal and acaricidal toxicant compounds, is well known in the literature. Insecticide collars generally consist of flexible plastic strips impregnated with insecticide. The usual production of these collars--by extrusion--subjects the insecticide to high temperatures during the extrusion step, often limiting the effectiveness of the collar due to degradation of the insecticide. The insecticide is released from the collar by evaporation of volatile insecticides or by diffusion in the case of non-volatile insecticides. Highly volatile insecticides are of course, sensitive to heat degradation, while a large portion of the non-volatile compounds remain trapped in the polymer of the plastic collar.
U.S. Pat. No. 4,879,117 by Rombi teaches a novel design for a collar which contains a central core of porous material impregnated with insecticide and plasticizer. The core is then covered with a thin polymer. The plasticizer aids the insecticide in diffusing through the polymer to the animal, [p. 3, lines 5-14]. The advantage of this collar is that retention of the active ingredient is greatly reduced. However, since the majority of collars are currently made by extrusion processes, this process requires retooling of the manufacturing plant to accommodate this more complex manufacturing process. Although Rombi '117 generally discloses the use of insect growth regulators with the disclosed device, there is no suggestion that high molecular weight insect growth regulator type materials can be used in a conventional collar design, nor is there any suggestion that pyriproxifen could be successfully formulated for sustained release.
U.S. Pat. No. 4,150,109 by Dick et al. employs the insecticides Diazinone and Diazoxone in conjugation with plasticizers and vegetable oils in heat extruded plastic collars. The insecticide is present in the collar at concentrations of 10-20%, (p. 31, lines 11-35). The plasticizer contained in the collar aids in the diffusion of the insecticide through the polymer of the collar to the animal. However, Dick does not suggest use of insect growth regulator type materials with the plasticizer and stabilizers disclosed therein.
Certain substituted heterocyclics of known insecticidal and ovicidal activity, including pyriproxifen, are disclosed in U.S. Pat. Nos. 4,970,222, 4,879,292 and 4,751,223. However, these nitrogen-containing heterocyclic compounds have not heretofore been suggested as being suitable for incorporation into and release from controlled release devices over long periods to affect administration of these ovicidal agents wherein an ovicidally effective dose is available to the target ectoparasite when the target ectoparasite first climbs or jumps onto the host and for months thereafter, and at low, continuous, constant, effective dosage.
The pyriproxifen and related molecules are disclosed, for example, in Nishida et al, U.S. Pat. No. 4,970,222. Nishida teaches the use of this class of compounds in the treatment of the Coleoptera, Lepidoptera, Hemiptera, Dictyoptera and Diptera orders of the class Insecta and the spider mite Tetranychidae belonging to the order Acarina of the class Arachnida. Nishida provides working examples for the control of the wax moth, [p. 49, lines 24, 37], the common mosquito, [p. 49, lines 52-54, p. 51, lines 65-66, and p. 52, lines 5-20], the common housefly, [p. 53, lines 64, 65 and p. 54, lines 24-31], and carmine spider mites, [p. 53, lines 36, 54-60]. Methods of treatment include the use of compositions in the form of emulsifiable concentrates, dusts, granules, wettable powders and fine granules, [p. 45, lines 45-49], which can be applied through means such as spraying, smoking, soil treatment, or in combination with animal feed, [p. 47, lines 26-28]. Nishida does not contemplate the use of pyriproxifen or pyriproxifen-like compounds in the control of flea or tick infestations. Neither are topical applications to phyla other than the Arthropoda listed above recognized.
U.S. Pat. No. 4,973,589 by Barnett et. al. teaches the systemic use of insect growth regulators for the control of fleas only, where the compounds are administered orally, parenterally or by implant, [p. 15, lines 50-55]. Barnett does not describe the use of the pyriproxifen-related compounds. U.S. Pat. No. 4,166,107 by Miller et al. teaches the systemic use of the insect growth regulators methoprene and difiubenzuron in sustained release bolus formulations for the control of livestock pests.
The existing technology referenced above has not heretofore been employed for sustained low level controlled release of the 2-pyridine class of insect growth regulators for topical application to pet animals to achieve control of ectoparasitic insects through sterilization of these ectoparasitic insects and their eggs (when laid on the host). The low solubility, relatively large molecule and relatively low vapor pressure of pyriproxifen compared with some insecticidal and acaricidal toxicants, have led to predictions that formulation of effective controlled release devices for delivery of insect growth regulators at constant ovicidally effective low doses would be difficult. Consequently, ovicidal activity in a target species has been reported for only for methaprene in sustained release type materials.